Using all-atom simulations in explicit solvent to study aggregation of amphipathic peptides into amyloid-like fibrils

Here, we perform all-atom molecular dynamics simulations in explicit solvent to study the aggregation of amphipathic peptides into amyloid-like fibrils. We use large simulation boxes containing more than 200,000 atoms and including 50 peptides to account for peptide concentrations of the order of 30 mM. Six different peptide sequences are studied in this work. We show that when long simulations (2–3 μs) are performed, a positive correlation is observed between experiments and simulations. In particular, peptide sequences that do not form fibrils in experiments show a low propensity to form inter-peptide hydrogen bonds and β-structures, and vice versa. Simulations are also performed at different temperatures and NaCl concentration to highlight the importance of hydrophobic and electrostatic interactions on aggregation. The rate of fibril formation in our simulations increases with increasing temperature for amphipathic peptides made from highly hydrophobic amino acids. This phenomena is related to the strength of hydrophobic interactions that enhances with increasing temperature. Electrostatic interactions may be responsible for the preference of anti-parallel β-sheets in our simulations. However, screening these interactions with NaCl favors aggregation of amphipathic peptides made from less hydrophobic amino acids. The sequence of events leading to fibril growth in our simulations is also discussed.